This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our work is designed to identify the defect in the host immune response responsible for the inability of the remaining 80% to naturally clear HCV infection. We hypothesized that the cellular immune response is the principal determinant of whether HCV infection is acutely resolved or establishes persistence and we are seeking to elucidate and understand the essential components of an effective anti-HCV immune response. We are utilizing a large cohort of chronically infected human patients, as well as novel cell culture systems to dissect the anti-HCV immune response. We began building a cohort of patients undergoing liver transplantation for HCV related liver failure. This cohort comprises patients with a wide variety of fibrosis scores, not just cirrhosis. We were able to obtain large wedge samples from both the donor and recipient livers allowing comprehensive phenotypic and some functional analysis of the intrahepatic immune response to HCV. We identified phenotypic markers of anti-HCV liver infiltrating T cells that correlate with T cell dysfunction that may be targets for immune augmentation. We described an increased propensity of HCV specific cells to undergo massive apoptosis in the peripheral blood during acute infection and in the liver during chronic infection as well as a critical balance between molecules facilitating immune stimulation and inhibition. The ability to follow transplant patients longitudinally is critical, since the majority will again manifest HCV viremia. This unique window into the infection timeline is allowing us unprecedented assessment of the immune response.